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A multicentre randomised phase III trial in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) was undertaken to compare the therapeutic activity and toxicity of a cisplatin/carboplatin-etoposide-vinorelbine combination with that of a cisplatin-etoposide regimen. Patients with advanced (stage IIIB-IV) NSCLC were randomised, after stratification for stage (IIIB-IV) and performance status (0-1 and 2), to receive either (A) CDDP 40 mg m-2 + VP16 100 mg m-2 on days 1-3 as standard treatment or (B) CBDCA 250 mg m-2 on day 1 + CDDP 30 mg m-2 on days 2 and 3 + VP16 100 mg m-2 on days 1-3 + NVB 30 mg m-2 on day 1. Therapy was recycled on day 29 in both arms. We hypothesised a 15% minimum increment in the response rate with the experimental regimen over the 25% expected activity rate of the standard regimen. A two-stage design was chosen, which permitted the early termination of the trial (after the accrual of 52 patients in each arm) if the difference in response rates between the two regimens was less than 3% at the end of the first stage. A total of 112 patients (arm A = 57, arm B = 55) were enrolled in the study (53 with stage IIIB and 59 with stage IV), of which 105 eligible patients were evaluable for response on an "intention to treat' basis. Seven patients were excluded because they did not fulfil the inclusion criteria. Fifteen responses were observed in arm A (28%, 95% CI = 17-42) and 13 (one complete) in arm B (25%, 95% CI = 13-37). On multivariate logistic analysis, treatment did not affect the response rate, while stage IV and performance status 2 were significantly associated with a lower probability of response. Median survivals were similar in the two arms (31 vs 27 weeks). The experimental regimen was associated with an extremely poor median survival in patients with poor performance status (21 weeks). On Cox analysis, treatment failed to show a significant impact on survival: stage IV (relative risk = 1.6. CI = 1.0-2.6, P = 0.036) was the only prognostic variable significantly associated with a worse survival outcome and, although poor performance status adversely affected survival, this effect did not reach the level of statistical significance (relative risk = 1.6, CI = 0.98-2.5; P = 0.063). There were no significant differences in non-haematological toxicities between the two arms, although three patients in the control arm had to discontinue the treatment because of the persistence of severe nephrotoxicity (two patients) or neurotoxicity (one patient). In contrast, a significant increase in both neutropenia and thrombocytopenia was observed in the experimental arm. Four treatment-related deaths were registered in arm B (two due to neutropenic sepsis, one to myocardial failure and one to acute renal failure) compared with one toxic death (acute renal failure) in arm A. In view of these results, the trial was stopped and the null hypothesis (< 15% increase in response rate with the experimental regimen) has been accepted. Therefore, our combination does not deserve further evaluation as first-line treatment in advanced NSCLC patients. As our data suggest that an aggressive chemotherapy might have a negative impact on survival of patients with poor performance status, trials to evaluate the activity of new regimens should be conducted separately for each subset of patients with different performance status.

BACKGROUND Preclinical data suggested that alpha-interferon (IFN) may potentiate chemotherapy cytotoxicity. METHODS A prospective multicentric randomized trial was initiated to assess the clinical benefit of adding recombinant alpha-2-IFN to combination chemotherapy in patients with metastatic non-small cell lung cancer. A total of 182 patients were randomized to receive either cisplatin-epidoxorubicin-cyclophosphamide (CEP) combination chemotherapy (cisplatin, 60 mg/m2; epidoxorubicin, 50 mg/m2; and cyclophosphamide, 400 mg/m2 intravenously) alone on day 1 or the same chemotherapy plus recombinant alpha-2-IFN at the dose of 5 MU intramuscularly from day -2 to +4, then 3 times weekly. RESULTS The median survival was 6 months in the CEP plus IFN arm versus 5.5 months in the control arm. The log-rank test showed a marginal statistically significant difference (P = 0.045) in favor of CEP chemotherapy, which disappeared when survival curves were adjusted for prognostic factors. Progression-free survival was similar in the two treatment arms. Considering all eligible patients, the response rate was 7.6% in the CEP arm versus 18.9% in the CEP plus IFN arm (P = 0.042). Nearly 40% of the patients receiving IFN had grade 3-4 nadir leukopenia versus 15% in the control arm (P = 0.01) and 12.5% versus 4.2% had grade 3-4 thrombocytopenia. Apart from the usual constitutional symptoms, IFN was also responsible for increased emesis and mucositis. CONCLUSIONS This study indicates that the addition of recombinant alpha-IFN to CEP chemotherapy can increase response rate and toxicity to treatment without a positive effect on progression-free survival and survival.

Two hundred sixteen patients with unresectable non-small cell lung carcinoma were randomly allocated to receive etoposide (120 mg/m2, days 1-3) either alone or in combination with high-dose cisplatin (60 mg/mz, days 1-2). The patients’ distribution and characteristics were similar in the two treatment arms. The objective response rate for etoposide was 7% versus 25.8% for etoposide plus cisplatin (P < 0.005). Median progression-free survival in etoposide arm was 3.5 months versus 5 months in the combination arm (P = 0.43). The median survival time for etoposide was 6 months compared with 8 months for etoposide combined with cisplatin (P = 0.87). Significantly more nausea/vomiting (P < 0.005), serum creatinine elevation (P < 0.0051, hearing loss and/or tinnitus (P < 0.005), peripheral neuropathy (P < 0.005), leukopenia (P < 0.025), and anemia (P < 0.005) occurred in the etoposide plus cisplatin arm. No statistically significant difference was recorded between the two arms in terms of performance status changes. In conclusion the addition of high-dose cisplatin to single-agent etoposide significantly increases the chance of obtaining tumor response in advanced non-small cell lung cancer at the cost of an increased toxicity without any significant long-term impact on survival and progression-free survival. Cancer 66:130-134,1990. HE TREATMENT of inoperable non-small cell lung

OBJECTIVE: This phase III study was aimed at evaluating whether the addition of gemcitabine (G) to vinorelbine (V) could improve the survival and quality of life (QoL) of elderly patients with advanced NSCLC. PATIENTS AND METHODS: Patients with advanced NSCLC, aged >or=70 years, were randomly allocated to receive V 30 mg/m(2) on days 1 and 8 every 3 weeks or G 1200 mg/m(2) plus V 30 mg/m(2) on days 1 and 8 every 3 weeks. Survival was the main end point of the study. The estimated sample size was 120 patients per arm, but an interim analysis of survival was planned on the first 60 patients per arm. RESULTS: In May 1999, an interim analysis was performed with the survival data of the first 120 eligible patients (V(arm)=60, G+V(arm)=60). Forty-nine patients had stage IIIB disease and 71 patients stage IV disease, median potential follow-up of 14 months (range; 3-22), 93 patients had died (G+V(arm)=41, V(arm)=52). Median survival time (MST) was 29 weeks and projected 1-year survival was 30% in the G+V(arm); these values were 18 weeks and 13% in the V(arm). At multivariate Cox analysis, the risk of death in the G+V(arm) compared with V(arm) was 0.48 (95% C1=0.29-0.79; P

PURPOSE: To evaluate whether the addition of gemcitabine (G) to vinorelbine (V) improves survival and quality of life (QoL) among elderly patients with advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with NSCLC aged ≥ 70 years with advanced disease were randomly allocated to receive V 30 mg/m2 on days 1 and 8 every 3 weeks or G 1,200 mg/m2 + V 30 mg/m2 on days 1 and 8 every 3 weeks. The estimated sample size was 120 patients per arm, but an interim analysis of survival was planned based on the first 60 patients per arm. RESULTS: In May 1999, the survival data were analyzed of 120 eligible patients (V group = 60; G + V group = 60) who had been randomized from June 1997 to February 1999. Forty-nine patients had stage IIIB disease, and 71 had stage IV. At a median potential follow-up of 14 months (range, 3 to 22 months), 93 patients had died (G + V group = 41; V group = 52). In the G + V group, median survival time was 29 weeks and projected 1-year survival was 30%; these values were 18 weeks and 13% in the V group. According to multivariate Cox analysis, the risk of death in the G + V arm compared with the V arm was 0.48 (95% confidence interval, 0.29 to 0.79; P < .01). Combination therapy was also associated with a clear delay in symptom and QoL deterioration. The overall response rates were 22% and 15% in the G + V and V groups, respectively. CONCLUSION: In elderly patients with NSCLC, G + V treatment is associated with significantly better survival than is V alone.

Aims and background The treatment of elderly patients with metastatic solid tumours is still a debated problem. Patients over 75 years are generally excluded from combination chemotherapy trials because of higher toxicity. Several clinical studies have shown that weekly low dose epirubicin is a well tolerated and effective treatment for elderly cancer patients (breast, prostate, lung). Methods We report a study of patients aged between 75 and 85 years affected by metastatic anthracyclines-sensible carcinomas, to assess the tolerance of epirubicin given weekly at a dose of 25 mg/m2. Results 25 patients (13 males, 12 females; ECOG P.S. 0-2) entered the study and were evaluable for side effects. One-hundred and ninety-six cycles of therapy have been administered. Side effects were never severe. Mucositis (9 patients), leucopenia (7 patients), anemia (5 patients) were usually of grade 1 or 2. Grade 1 cardiotoxicity (tachycardia) was observed in only one case. Grade 3 toxicity consisted in anemia (1 patient) and mucositis (1 patient), while grade 4 toxicity never occurred. Nineteen patients were evaluable for response: 0 CR, 4 PR (1 lung, 3 breast), 8 SD (3 lung, 3 breast, 2 prostate) have been observed. Compliance was encouraging and the majority of patients showed a decrease in symptoms and an improvement in performance status. Conclusions Weekly low-dose epirubicin is a very well tolerated treatment in elderly cancer patients. In view of the negligible toxicity encountered, it could be of utility to test this regimen in patients aged 75 years or older, affected by anthracyclines-sensible metastatic tumors, also to assess activity.

PURPOSE: Because both cisplatin-paclitaxel and cisplatin-gemcitabine combinations are generally considered to be among the most active regimens in non–small-cell lung cancer (NSCLC) patients, this study aimed to determine the maximum-tolerated dose (MTD) of paclitaxel when combined with fixed doses of cisplatin and gemcitabine in advanced NSCLC patients and aimed to define the therapeutic activity of this new regimen. PATIENTS AND METHODS: From October 1996 to September 1998, 75 patients with stage IIIB-IV NSCLC, who were either chemotherapy-naive (65 patients) or who had been pretreated (10 patients), received fixed doses of cisplatin (50 mg/m2) and gemcitabine (1,000 mg/m2) and escalating doses of paclitaxel in a 1-hour infusion, all on days 1 and 8, every 3 weeks. RESULTS: Five different paclitaxel doses were tested, for a total of 275 cycles delivered. The escalation was stopped at the paclitaxel dose of 75 mg/m2 in pretreated patients, whereas it continued to 150 mg/m2 in chemotherapy-naive patients. A total of 65 chemotherapy-naive patients were treated. A paclitaxel dose of 125 mg/m2 was recommended for phase II, and a total of 39 patients were treated at this level, for a total of 158 cycles delivered. No treatment-related deaths occurred. Five patients were hospitalized because of sepsis, and packed RBC transfusion was required in 13 patients. Grade 4 neutropenia and thrombocytopenia occurred in 23 (31%) and eight (11%) patients, respectively. Overall, 74 of the 75 patients were assessable for response. Four complete (CR) and 38 partial (PR) responses were recorded, for an overall response rate (ORR) of 57%. Three of the ten pretreated patients achieved a PR, compared with four CRs and 35 PRs in the 64 chemotherapy-naive patients (ORR, 61%). Thirty-eight of 39 patients included in phase II were assessable for response and quality of life (QOL) (one patient's disease was not measurable). Two CRs and 24 PRs were recorded in this group, for an ORR of 68% (95% confidence interval, 51% to 82%). The QOL score improved in 27 of 38 (71%) patients. The median survival time was 15 months in the 65 chemotherapy-naive patients, but it had not yet been reached in the 39 patients included in phase II, for whom the 1-year projected survival was 70%. CONCLUSION: The cisplatin-gemcitabine-paclitaxel combination is a feasible and well-tolerated approach in advanced NSCLC patients. Both a major response and a QOL improvement can be obtained in a high proportion of patients, with a median survival time exceeding 1 year. A phase III trial comparing this combination with other effective regimens is under way.

A Multidimensional Performance Model of a Spark Ignition Engine Characterized by a Single Step Reaction to Equilibrium Abstract-A new multidimensional model of a spark ignition engine has been developed. The main features of this model are its two-dimensional computational scheme, the assumption of equilibrium conditions for the thermodynamical properties, and the automatic determination of the initial conditions. This approach enables the number of free parameters to be considerably reduced with respect to similar programs currently available, thus ensuring an overall increase in the reliability of the entire computational scheme.